A regulatory role for porphobilinogen deaminase (PBGD) in delta-aminolaevulinic acid (delta-ALA)-induced photosensitization?
As an initial approach to optimize delta-aminolaevulinic acid (delta-ALA)-induced photosensitization of tumours, we examined the response of three enzymes of the haem biosynthetic pathway: delta-ALA dehydratase, porphobilinogen deaminase (PBGD) and ferrochelatase. Only PBGD activity displayed a time- and dose-related increase in tumours after intravenous administration of 300 mg kg(-1) delta-ALA. The time course for porphyrin fluorescence changes, reflecting increased production of the penultimate porphyrin, protoporphyrin IX (PPIX), showed a similar pattern to PBGD. This apparent correlation between PBGD activity and porphyrin fluorescence was also observed in four cultured tumour cell lines exposed to 0.1-2.0 mM delta-ALA in vitro. The increase in PBGD activity and PPIX fluorescence was prevented by the protein synthesis inhibitor cycloheximide. As the apparent Km for PBGD was similar before and after delta-ALA, the increase in PBGD activity was attributed to induction of enzyme de novo. These observations of an associated response of PBGD and PPIX imply that PBGD may be a rate-limiting determinant for the efficacy of delta-ALA-induced photosensitization when used in photodynamic therapy.
Gibson
S L
SL
Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Cupriks
D J
DJ
Havens
J J
JJ
Nguyen
M L
ML
Hilf
R
R
D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D005260:Female; D005294:Ferrochelatase / Q000378:metabolism; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D000623:Porphobilinogen Synthase / Q000378:metabolism; D011166:Porphyrins / Q000032:analysis; D051381:Rats; D013050:Spectrometry, Fluorescence; D014407:Tumor Cells, Cultured
D017319:Photosensitizing Agents; D011166:Porphyrins; D000622:Aminolevulinic Acid; D003513:Cycloheximide; D011163:Hydroxymethylbilane Synthase; D000623:Porphobilinogen Synthase; D005294:Ferrochelatase